FI83520C - Process for the preparation of therapeutically useful 2-phenylpyrano / 2,3-b / pyridines - Google Patents

Description

1 83520

Process for the preparation of therapeutically useful 2-phenylpyrano [2,3-b] pyridines

The invention relates to a process for the preparation of therapeutically useful 2-phenylpyrano [2,3-b] pyridines of the formula I

R "10 * il / T2 \ (I)

R

wherein R, R 'and R "are each hydrogen or lower alkyl of 1 to 4 carbon atoms; X is hydrogen, chlorine, bromine, alkylthio, alkylsulfinyl, alkylsulfonyl, hydroxy or benzoyl; and Y is hydrogen, halo, di- or trichloro , alkyl, alkoxy, methylenedioxy or phenoxy.

EP 4,579 discloses flavans or derivatives thereof useful as antiviral agents in which benzopyran structures are present instead of pyranopyridine structures.

All references to the aforementioned alkyls or lower alkyl groups, either alone or as part of a longer group, such as alkylthio or alkylsulfonyl, or implicitly as part of alkoxy (alkyloxy), include compounds having 1 to 4 carbon atoms in the alkyl group. Such alkyl groups or alkyl-containing groups include methyl, ethyl, propyl, butyl, methylthio, ethylthio, butylthio, methylsulfinyl, ethylsulfinyl, butylsulfinyl, methylsulfonyl, ethylsulfonyl, butylsulfonyl, methoxy, ethoxy, propoxy. Substituent 35 support X in the above structural formula may be located at any available position on the pyridine ring (i.e., at the 5-, 6-, or 7-positions in the pyrano [2,3-b] pyridine structure), although pyrano [2,3 -b] pyridine 6-azera is preferred. The halo substituents referred to above for Y are fluorine, chlorine or bromine. The Y group may also be a polysubstitution on the phenyl ring, such as dichloro, trichloro or methylenedioxy. In the case of dichloro or trichloro substitutions, all isomers can be used, although 4-chlorophenyl and 3,4-dichlorophenyl compounds are preferred. In the case where 10 Y is methylenedioxy, this substituent is in the 3,4-position of the phenyl ring.

The compounds to be prepared according to the invention include e.g. the following: 2- (3,4-dichlorophenyl) -3,4-dihydro-6- (methylsulfonyl) -15 2H-pyrano [2,3-b] pyridine; 6-bromo-2- (3,4-dichlorophenyl) -3,4-dihydro-2H-pyrano [2,3-b] pyridine; 6-bromo-2- (3,4-methylenedioxyphenyl) -3,4-dihydro-2H-pyrano [2,3-b] pyridine; 6-bromo-2- (2,4-dichlorophenyl) -3,4-dihydro-2H-pyrano- [2,3-b] pyridine; 2- (3,4-dichlorophenyl) -3-methyl-3,4-dihydro-6- (methylsulfonyl) -2H-pyrano [2,3-b] pyridine; 2- (3,4-dichlorophenyl) -4-methyl-3,4-dihydro-6- (methyl-sulfonyl) -2H-pyrano [2,3-b] pyridine; 2- (3,4,5-trichlorophenyl) -3,4-dihydro-6- (methylsulfonyl) -2H-pyrano [2,3-b] pyridine; 2- (4-methoxyphenyl) -3,4-dihydrogen · 6-methylsulfonyl} -2H-pyrano [2,3-b] pyridine; 2- (3,4-dichlorophenyl) -3,4-dihydro-6- (n-butylsulfonyl) -2H-pyrano [2,3-b] pyridine; and 7-chloro-2- (3,4-dichlorophenyl) -3,4-dihydro-2H-pyrano- [2,3-b] pyridine.

Certain advantages have already been set forth in defining the above substituent groups. In addition to and independently of these, there are the following 3,83520 advantages: The compounds in which R, R 'and R "are hydrogen are preferred compounds of the invention.

Another preferred group are those compounds wherein X and Y 5 are other than hydrogen.

- A further preferred group are those compounds in which X and Y are other than hydrogen, while R, R 'and R "are each hydrogen.

A further preferred group of compounds are those in which X 10 is chlorine, bromine or methylsulphonyl in the 6-position of the pyranopyridine structure.

A further preferred group of compounds are those in which Y is 4-chloro or 3,4-dichloro.

The process according to the invention for the preparation of the compounds of the formula I is characterized in that a suitable alcohol having the following structural formulas

R "OH R

20 R (II)

OH

Ik \ (m)

v N ^ 0CH3 V

Wherein X, Y, R, R 'and R "are the same as defined above and Q is methoxy or chlorine, cyclized using hydrobromic acid and acetic acid to 2-methoxypyridines or a strong base when Q is chlorine, followed optionally if the resulting product is a compound having 35 double bonds at the 3,4-position is catalytically reduced with 4,83520 hydrogen and Raney nickel to give the corresponding saturated compounds.

When 2-methoxypyridine is involved in the reaction, the compound is first reacted with hydrobromic acid 5 to cleave the ether and the cleavage product is reacted with an acid such as acetic acid to effect cyclization to give pyranopyridine. When Q is chlorine, the alcohol is exposed to a strong base to effect cyclization. In the case of starting material III, the slyl alcohol must first be isomerized to an allyl ion analogous to the allyl ion obtained from structure II before the cyclization takes place. In cases where the intermediate alcohol is obtained by reduction from the corresponding ketone, it is usually more convenient to carry out the reduction to obtain the alcohol and then immediately cyclize the alcohol, as shown, without special isolation. However, the alcohol is obtained in the process and could be isolated in pure form and cyclized by a stepwise process if desired.

When the final product obtained above contains unsaturation at the 3,4-position of the pyranopyridine ring, it can be catalytically reduced with hydrogen and Raney nickel to give the corresponding 3,4-dihydro compound, or the double bond can be isomerized to the 2,3-position with base 25, such as 1,8-diazobicyclo [5.4.0] undec-7-ene.

The cyclization step described above is used in the preparation of the compounds of the invention at some points. Numerous methods are available for the preparation of the starting alcohol and these can be summarized in the following schemes:

Chart I:

To prepare compounds of structural formula ττχ above, the appropriate cinnamaldehyde is reacted with a lithium compound of formula IV

5 83520 γ / Li π (IV) 5 OCH3 in an inert solvent by standard methods. The disclosed lithium compound was originally prepared in situ from the corresponding 3-bromopyridine using reagents such as 10 n-butyllithium in ether at -70 ° C. The bromo compound shown itself is obtained by bromination of the appropriate 2-methoxy-5-X-pyridine in acetic acid.

Figure II:

The lithium compound (IV) shown in Scheme I can also be used in the preparation of other type II alcohol intermediates wherein Q is methoxy. More specifically, lithium compound IV is reacted with dimethylformamide to replace lithium with a formyl group. The resulting pyridine-3-carboxaldehyde is condensed with the appropriate acetophenone in the presence of a strong base by Claisen-Schmidt condensation to give the echo. The carbonyl group of the chalcone is then reduced with a reagent such as sodium borohydride to give the alcohol of the general type shown in Structural Formula II above.

Alternatively, the olefinic double bond of chalcone can first be reduced with hydrogen and Raney nickel, followed by reduction of the carbonyl group as shown. This gives a saturated alcohol which can then be cyclized to give 3,4-dihydropyranopyridine.

In a variation of this chalcone process, the lithium compound IV can be reacted with acetonitrile or acetaldehyde followed by oxidation to give the corresponding 3-acetylpyridine. This acetyl-35-pyridine is then reacted with the appropriate substituted aldehyde by Claisen-Schmidt condensation to give the cathon as described above, although it is an isomer ("inverted") cation, i.e., reduction of the carbonyl group of the chalcone gives the type. III an alcohol similar to that previously shown in Scheme I 5.

Figure III:

In another method for preparing the previously mentioned intermediate alcohols, the 3-bromide compound used in the preparation of the lithium compound IV can be used in the Heck reaction. This means that bromine pyridine is reacted with ethenyl alcohol of formula V.

ril L TY

15 I (V)

OH

in the presence of palladium acetate and an inert solvent to give a ketone of formula VI

The carbonyl group of the ketone is then reduced to the type II alcohol previously described using standard materials such as sodium borohydride. The disclosed VI chain can also be reacted with an alkyl Grignard reagent (RMgCl) to give a tertiary tertiary alcohol. Such a method can be used to prepare those compounds in which E is alkyl.

Scheme IV; 35 In a method which may be considered as a variation of the scheme, the Heck reaction may be performed using 7,83520 ethenyl alcohol V and 2-chloro-3-iodo-5- (methylsulfonyl) pyridine to give a ketone analogous to VI, except that the methoxy group has been replaced by 2-chloro. This ketone is then reduced to the corresponding alcohol using diisobutylaluminum hydride at low temperature, and the resulting alcohol is cyclized as previously described for 2-chloropyridines. The necessary iodine compound used in this method can be obtained starting from 2,5-bis (methylsulfonyl) pyridine and treating it with sulfuric acid to hydrolyze the 2-substituent, followed by iodination with potassium iodide / potassium iodate using a method which gives 5- (methylsulfonyl) -2 (lH) -pyridinone. This is then treated with phosphorus oxychloride to give the corresponding 2-chloropyridine. The corresponding compound having bromine instead of iodine can be obtained by using a brominating agent in place of the iodinating agent in the above method, followed by conversion to the 2-chloro compound. The resulting 3-bromo compound can then be used in the same manner as the 3-iodo compound.

In addition to the general method previously described, certain previously described end products may also be used to make other products. More specifically, the final product where X is 6-bromine can be reacted with an alkyllithium such as butyllithium at -100 ° C to give the corresponding 6-lithium derivative. This lithium derivative can then be reacted in situ to give a number of other 6-substituted products. Thus, reaction of the lithium compound with dialkyl sulfide-30 gives the corresponding 6-alkylthio compound. This alkylthio compound can then be oxidized to the corresponding alkylsulfinyl or alkylsulfonyl compounds using a suitable oxidant.

Reaction of the lithium compound with benzonitrile or acetonitrile gives the corresponding 6-benzoyl or 6-acetyl compound. Alternatively, the lithium compound β 83520 can be reacted with acetaldehyde to give the corresponding alcohol, after which this alcohol is oxidized to give the corresponding acetyl compound. To prepare the 6-alkyl compound, the lithium compound is reacted with an alkyl halide such as methyl iodide.

In another method, the lithium compound can be simply treated with methanol to give the corresponding 6-hydrogen compound. In yet another reaction, the lithium compound can be reacted with butyl borate, followed by treatment with an oxidizing agent such as peroxide to give the corresponding hydroxy compound. Reaction of the hydroxy compound with dimethyl sulfate under temporal conditions affords the corresponding 6-methoxy compounds.

The production methods of this invention were generally described above for the preparation of only 6-substituted compounds, as such substitution is most readily obtained. However, similar methods can be used to prepare isomeric compounds in which the substituent is at another position in the pyridine ring. However, certain specific methods may be preferred for the preparation of such isomeric compounds. Thus, it is possible to start with 2-chloro-6-methoxy-pyridine and subject it to a series of reactions shown in Schemes I or II to give the final 6-bromo-7-25 chlorine product and then selectively remove the 6-bromo atom by catalytic hydrogenation. Alternatively, the final 6-bromo product can be lithiated at the 5-position, after which various groups are introduced into this position by standard methods followed by removal of the 6-bromo atoms.

The compounds of the invention are useful as antiviral agents. Thus, the compounds disclosed herein, i.e., anti-viral compounds of formula I, can be used to inhibit viral replication by exposing the virus or. preferably, the host cells of the virus 35 are contacted with an effective amount of a suitable compound of interest.

9,83520

Conventional compositions may contain from about 0.00001% to about 99% by weight of active ingredient in association with a pharmaceutically acceptable carrier. Typically, in those combinations containing a small percentage of the active compound, the pharmaceutically acceptable carrier is in liquid form; thus, a composition containing 0.00001% by weight or less of active ingredient is equivalent to a composition containing about 0.1 ug or less of active ingredient per 10 milliliters of carrier.

The antiviral compounds prepared according to the invention have been found to be very effective against picornaviruses, i.e. against small ribunocleic acid viruses. Picornaviruses include 15 viruses such as Enteroviruses, Rhinoviruses, and a number of viruses that cause plant diseases. There is variation from compound to compound in antiviral efficacy and in the spectrum of antiviral activity and toxicity and side effects.

20 Ko. the antiviral activity of the compounds was demonstrated using the following tissue culture assay procedure.

HeLa cells (CIBCO, Grand Island, New York) were grown and maintained at 36 ° C in Corning 75 cm 2 tissue culture flasks using Eagles Minimum Essential Medium

With Earles Salts supplemented with 1% antibiotic stock. 7-10% heat-inactivated fetal calf serum was added to the medium for cell growth (medium) and the concentration was reduced to 1-2% cell content (medium). Cell strains were stored in liquid nitrogen and used at levels of 10-100.

HeLa cells were transferred to 24-well microtiter plates at concentrations of 1.0 to 1.3 x 10 5 cells per well 35 in 1.0 ml of medium. Grown for 24 hours at 36 10 83520 ° C in humidified CO 2 (5% CO 2, 95% air) in an incubator, after which the cultures were 60-75% monolayer and ready for use. 2 mg of each test compound was mixed with 0.1 ml of acetone, followed by the addition of 10 ml of medium to give a stock concentration of 200 pg of compound / ml. Dilutions were then made in the same medium to obtain different experimental concentrations. HeLa cell cultures in 24-well microtiter media were dried and 1.0 ml of compound-containing or compound-free medium was added. The appropriate monolayer cells were then treated with 0.1 ml (10-100 TCID50) of virus. Cell cultures were incubated at 33 ° C or 36 ° C in a humidified CO 2 incubator and examined under a microscope 48, 72 and 96 hours after virus addition for compound cytotoxicity and viral cell disease (CDE). Viral CPE was assessed as follows: - = no CPE; +1 = 20% CPE; +2 = 40% CPE; +3 = 60% CPE; +4 = 80% CPE; or +5 = 100% CPE The lowest concentration of a compound that reduced viral CPE by 50% or more compared to a reference compound was considered the lowest inhibitory concentration (MIC50) of this compound.

Using the above method, the compounds of the invention were tested against RV-IA, RV-2, RV-9, RV-39 and RV-64 viruses. As previously reported, variations in activity were observed, but most of the compounds were active against all viruses with a MIC50 of 1.3 pg / ml or less.

Exceptions in this respect are 6- (butylthio) -2- (3,4-dichlorophenyl) -3,4-dihydro-2H-pyrano [2,3-b] pyridine (active only on RV-2 and RV-39 against); 3,4-dihydro-6- (methylsulfonyl) -2-phenyl-2H-pyrano-35,2,3-b] pyridine (active against RV-2, RV-9 and RV-39; 2 , 5, 2.5 and 5 pg / ml, respectively); and il 83520 6-bromo-2-phenyl-2H-pyrano [2,3-b] pyridine (active against RV-1A only).

Some of the most active substances in the previous experiment were also tested against other viruses and were found to be active against the following viruses: RV-IB, RV-10, RV-13, RV-21, RV-29, RV-32, RV-33, RV- 44, RV-49, RV-55, RV-74, RV-89, RV-Hanks, Echo 6, Echo 12, Echo 30 and Entero 70.

The compounds of the invention were also tested in mice (400 mg / kg; oral) and the mouse serum was examined and found to contain significant amounts of test compound.

Due to their clear advantages (e.g. broad spectral antiviral activity at low concentrations of compound), preferred compounds of the invention are the following: 2- (3,4-dichlorophenyl) -3,4-dihydro-6- (methylsulfonyl) - 2H-pyrano [2,3-b] pyridine, 6-bromo-2- (3,4-dichlorophenyl) -3,4-dihydro-2H-pyrano-20 [2,3-b] pyridine and 6-chloro- 2- (3,4-dichlorophenyl) -3,4-dihydro-2H-pyrano [2,3-b] pyridine.

When using this compounds of the virus or the host cell of the virus are contacted with an amount of one or more compounds effective to inhibit the virus. Although the invention is not to be construed as limited to any particular theory of action, it appears that the compounds inhibit viruses in host cells rather than directly chemically or physically inactivating viral particles outside the cells. In antiviral applications in living environments, the assembly should be performed in a manner that ensures the continued presence of an effective amount of the compound when subsequent contact with host cells occurs. Preferably, the compounds are used by contacting the host cells with an effective amount (i.e., the amount that must be used to achieve a significant antiviral effect) of one or more antiviral compounds. Co-administration can be performed directly, such as by adding the compound to cells in tissue culture to prevent contamination of picornaviruses. The combination can also be performed by administering an antiviral dose of a compound of the invention to an animal, preferably a mammal. The compound can be administered to animals from outside the gastrointestinal tract, e.g., by intraperitoneal, subcutaneous, or intravenous injection; topically, e.g. as an aerosol or lotion, or administered intranasally or buccally; rectally or orally. In such applications, an effective amount of one or more compounds is dosed to the animal. Toxicity, mutagenicity, ease of administration, antiviral activity (efficacy), stability, compatibility with suitable carriers, etc. must be taken into account when selecting the compound or compounds for administration to animals in specific cases.

20 The exact amount of the compound or compounds to be used, i.e. compound or the amount of compounds sufficient to produce the desired effect will depend on various factors such as the compound used, the method of aggregation and administration, the size, age and species of the animal, the mode, time or frequency of administration, the virus or viruses involved, and -whether the compound is administered prophylactically or administered to an infected animal to prevent the virus causing the infection. In special cases, the amount to be administered can be ascertained by conventional dose range finding methods, for example, by examining the effects obtained with different doses using conventional viral analysis methods.

The compounds are preferably administered in the form of a composition comprising the compound in admixture with a pharmaceutically acceptable carrier, i.e., the carrier is chemically inert to the active ingredient and has no adverse side effects or toxicity under the conditions used. As previously reported, compounds administered to tissue cultures have significant antiviral activity at low concentrations, such as, e.g., 0.008 pg / ml 6-bromo-2- (3,4-dichlorophenyl) -3,4-dihydro-2H- pyrano [2,3-b] pyridine, which causes a 50% reduction in the disease effect of the cell when tested against the test virus RV-IA.

Such compositions may contain about 0.1 pg of 10 or less active agent per milliliter of carrier up to 99% by weight of active agent in association with a pharmaceutically acceptable carrier. Preferred are compositions containing from about 0.1 pg of active ingredient per milliliter of carrier to about 0.0025%, 0.05 to 15%, 0.25%, 0.5%, 1% to 10%, 25% or 50% by weight of the active compound in a pharmaceutically acceptable carrier.

The compositions may be in solid form, such as tablets, capsules, granules, premixes, food additives and concentrates, powders, granules or the like, also in liquid form, such as sterile injectable suspensions, oral suspensions or solutions. Pharmaceutically acceptable carriers may include additives such as surfactant dispersants, suspending agents, tablet binders, flavoring agents, and coloring agents. Suitable additives are disclosed in various publications, such as, for example, Remington's Pharmaceutical Manufacturing, 13th Edition, Mark Publishing Co., Easton, Pennsylvania, USA (1965).

The following examples are provided to illustrate the invention.

Example 1

To a stirred mixture of 14.8 g of 2,5-dichloropyridine in 50 ml of methanol was added 30 ml of a 20-35% methanol solution of sodium methoxide, and the mixture was heated under reflux under a nitrogen atmosphere. After 24-1420 hours, another 30 ml of sodium methoxide solution was added and heating under reflux was continued for a total of 68 hours. The precipitated sodium chloride was removed by filtration and the filtrate was concentrated at atmospheric pressure to about 1/4 of the original volume and partitioned between ether and water. The aqueous layer was extracted with ether and the combined ether layers were washed with brine, dried over potassium carbonate and concentrated in vacuo to a light brown oil. This residue was distilled to give 5-chloro-2-methoxypyridine as a colorless liquid boiling at about 82-84 ° C in 20 torr.

Repeating the above procedure using 2,5-dibromopyridine, the product obtained was 5-bromo-2-methoxy-15 pyridine, which boiled at about 99-101 ° C at 28 torr.

Example 2

To a stirred mixture of 2.5 g of anhydrous sodium acetate in 10 ml of acetic acid was added 4.3 g of 5-chloro-2-methoxypyridine, followed by the addition of 3.1 g of bromine in 10 ml of acetic acid. The mixture was heated to 80 ° C for 6 hours and then allowed to cool and stirred at 23 ° C for 64 hours. This was then partitioned between water and ether and the resulting ether layer was washed with 1N aqueous sodium hydroxide solution and then with 5% sodium bisulfite solution, dried over potassium carbonate and concentrated in vacuo to leave a brown solid. This residue was distilled from bulb to bulb and the material distilled at 140-150 ° C in 20 torr was obtained to give 3-30 bromo-5-chloro-2-methoxypyridine as a solid which melted. at about 45-47.5 ° C

Example 3

To a stirred solution of 111.4 g of 2-methoxypyridine in 500 ml of acetic acid. 164.1 g of 35 anhydrous sodium acetate was added portionwise over about 5 minutes to prevent the formation of lumps.

is 83520 179.3 ml of bromine were then added at a rate below 35 ° C. After this addition, the mixture was heated to 80 ° C for 6 hours and then stirred at 25 ° C for 16 hours. This mixture was poured into 25 liters of water and the resulting aqueous mixture was extracted with 2 x 500 ml portions of carbon tetrachloride. The organic extract was washed with 1N aqueous sodium hydroxide solution and 1N aqueous sodium bisulfate solution, dried over magnesium sulfate, filtered and concentrated under reduced pressure to leave a yellow liquid which solidified on cooling. The crude product was distilled through a short Vigreux column at 3 torr and after the pre-distillate, which was mainly 5-bromo-2-methoxypyridine, a fraction boiling at 110-112 ° C at 3 torr was collected. There was thus obtained 3,5-dibromo-2-methoxy-15 pyridine as a white solid, melting at about 49-51 ° C.

Example 4

A solution of 4.0 g of 3-bromo-5-chloro-2-methoxypyridine in 75 ml of anhydrous ether was cooled to 20-70 ° C under a nitrogen atmosphere. The resulting mixture was stirred rapidly, and 12.0 ml of 1.65 M n-butyllithium / hexane was added dropwise over about 5 minutes while maintaining the temperature below -70 ° C. The reaction mixture became homogeneous and after 15 minutes a solution of 3.0 g of 4-chlorocinnamaldehyde in 35 ml of ether was added dropwise, keeping the temperature below -60 ° C. The cold mixture was then poured into saturated aqueous sodium bicarbonate solution and the resulting mixture was extracted with ether. The ether layer was washed with saturated aqueous sodium chloride solution, dried over potassium carbonate and concentrated under reduced pressure to give (E) -5-chloro-α- [2- (4-chlorophenyl) ethenyl] -2-methoxy-3-pyridinemethanol as white needles. melting at about 135-139.5 ° C.

By repeating the above procedure using 3-35 bromo-5-chloro-2-methoxypyridine and 3,4-dichlorocinnamaldehyde, the product (E) -5-chloro-α- [2- (3,4-dichlorophenyl) was obtained. ) ethenyl] -2-methoxy-3-pyridinemethanol.

83520

Example 5

A mixture of 60.6 g of 3,5-dibromo-2-methoxypyridine in 900 ml of anhydrous ether was stirred under a nitrogen atmosphere and cooled to -78 ° C to give a thick mixture. Efficient stirring was used to prevent the solid starting material from adhering to the walls of the reaction vessel. The temperature was kept below -65 uC while 85 ml of 2.67 M n-butyllithium / hexane was added dropwise. The reaction mixture was homogeneous at the end of the addition and stirred for 15 minutes at -78 ° C. 45.6 g of 3,4-dichlorocinnamaldehyde in 200 ml of anhydrous tetrahydrofuran were then added dropwise while maintaining the temperature below -65 ° C. When the addition was complete, 100 ml of saturated aqueous sodium bicarbonate solution was added to the cold reaction mixture, which was then allowed to warm to about -40 ° C and then partitioned between ether and saturated aqueous sodium bicarbonate solution. , dried over potassium carbonate, filtered and concentrated to leave a pale yellow solid which was recrystallized from 2-propanol / ethyl acetate / hexane (1: 3: 5) to give (E) -5-bromo-α- ( 2- (3,4-dichlorophenyl) ethyl] -2-methoxy-3-pyridinemethanol, melting at about 149-150 ° C.

By repeating the above procedure using 3,5-dibromo-2-methoxypyridine and cinnamaldehyde, the product (E) -5-bromo-α- (2-phenylethenyl) -2-methoxy-3-pyridinemethanol was obtained.

30 Example 6

To a stirred mixture of 13.4 g of 3,5-dibromo-2-methoxypyridine in 200 ml of anhydrous ether at -70 ° C under a nitrogen atmosphere was added dropwise 29.2 ml of 1.71 M n-butyllithium / hexane for about 20 minutes 35 while keeping the temperature below -70 ° C. Stirring was continued for 10 minutes and then 7.7 ml of dime-style fo .'man> i (iia 11 - ·· '”--------- · - ··' · - ··· ·" 'was added. -55 17 83520 ° C and the mixture was allowed to cool again to -70 ° C. After 15 minutes, the cold solution was poured into excess 1 M aqueous hydrochloric acid, stirred until room temperature, then the 5 layers were separated and the aqueous layer was extracted. The combined ether layers were washed with saturated aqueous sodium chloride, dried over magnesium sulfate, filtered and concentrated to give a pale yellow solid, which was recrystallized from hexane to give pale yellow crystals melting at about 92-95 ° C. 5-bromo-2-methoxypyridine-3-carboxaldehyde The NMR spectrum showed the presence of another possible aldehyde isomer (3-bromo-2-methoxypyridine-5-carboxaldehyde), but the ratio of the two isomers was about 12: 1.

By repeating the above procedure using 3-bromo-5-chloro-2-methoxypyridine, the product 5-chloro-2-methoxypyridine-3-carboxaldehyde was obtained, melting at about 93-96 ° C.

20 Example 7

To a solution of 6.5 g of 5-bromo-2-methoxypyridine-3-carboxaldehyde in 30 ml of tetrahydrofuran under a nitrogen atmosphere was added 100 ml of methanol followed by 4.6 g of 4-chloroacetophenone. A solution of 6.6 g of 85% potassium hydroxide in 15 ml of water was then added. The mixture was heated to turn yellow and a thick precipitate formed. It was then stirred mechanically for about 1.5 hours until the temperature dropped again to about 25 ° C. It was then further cooled in an ice bath and neutralized by adding 20 ml of 5 M aqueous hydrochloric acid in small portions. The resulting thick mixture was poured into 400 ml of water, acidified to pH 1N with aqueous hydrochloric acid and then filtered. The wet product was boiled with 2-pro-.35 panol / ethyl acetate (3: 1), cooled and filtered. The solid filtrate was dried under reduced pressure to give (E) -3- (5-bromo-2-methoxy-3-pyridinyl) -1- (4-chloro-83520 riphenyl) -propen-X-one as a pale yellow solid which melted at about 168.5-171.5 ° C.

Repeating the above procedure using 4-methylacetophenone, the product obtained was (E) -3- (5-bromo-2-methoxy-3-pyridinyl) -1- (4-methylphenyl) -2-propen-1-one .

Similarly, using 3,4-dichloroacetophenone instead of 4-chloroacetophenone in the above procedure, the product obtained was (E) -3- (5-bromo-2-methoxy-3-pyridinyl) -1- (3,4-dichlorophenyl). ) -2-propen-1-one, Example 8

A stirred solution of 65.9 g of (E) -5-bromo-α- [2- (3,4-dichlorophenylethenyl] -2-methoxy-3-pyridinetinanol in 600 ml of acetic acid was heated to 100 °. To C in a nitrogen atmosphere to give a mixture of allyl acetate-15 and starting materials, then 60 ml of 48% aqueous hydrobromic acid was added all at once and the progress of the reaction was monitored by thin layer chromatography while maintaining the temperature at 95-100 ° C. after which the mixture was rapidly cooled to 20 ° C in a 20 ° C water bath and then poured into 2 liters of water.

Ether (1 liter) was used to extract the aqueous mixture. The ether layer was washed with 3 x 1000 mL portions of water, then with saturated aqueous sodium bicarbonate solution, and finally with saturated aqueous sodium chloride solution. Dry over magnesium sulfate, then filter the ether solution and concentrate under reduced pressure to give about 60 g of a dark yellow solid. This crude product was purified by dissolving it in methylene chloride and filtering the solution through silica gel to give, after evaporation of the solvent, a colorless solid. This was then recrystallized from absolute ethanol to give 6-promi-2- (3,4-dichlorophenyl) -2H-pyrano [2,3-b] pyridine, melting at about 100.5-301 ° C.

35 By repeating the above procedure and using appropriately substituted starting materials. The following products were obtained: 19 83520 6-bromo-2-phenyl-2H-pyrano [2,3-b] pyridine, m.p. 103.5-105 ° C; 6-chloro-2- (3,4-dichlorophenyl) -2H-pyrano [2,3-b] pyridii-ni; and 6-chloro-2- (4-chlorophenyl) -2H-pyrano [2,3-b] pyridine, m.p. about 91.5-93 ° C.

Example 9

The procedure of the first paragraph of Example 5 was repeated using 2-methyl-3-phenyl-2-propenal and 4-10 phenylbut-3-en-2-one in place of 3,4-dichlorocinnamaldehyde to give the corresponding pyridinemethanol product. This was then reacted with acetic acid followed by hydrobromic acid according to the procedure of Example 8 to give the following products: 6-bromo-3-methyl-2-phenyl-2H-pyrano [2,3-b] pyridine and 6-bromo -4-methyl-2-phenyl-2H-pyrano [2,3-b] pyridine.

Example 10

To a stirred mixture of 30 g of (E) -3- (5-bromo-2-methoxy-3-pyridinyl) -1- (3,4-dichlorophenyl) -2-20 propen-1-one in 275 ml of tetrahydrofuran and 260 In 1 ml of absolute ethanol, 6.0 g of sodium borohydride were added. The mixture was kept under a nitrogen atmosphere for 1 hour, after which the reaction mixture was partitioned between saturated aqueous 1N sodium hydroxide solution and ether. The ether layer .25 was washed with saturated aqueous sodium chloride solution, dried over sodium sulfate and concentrated in vacuo to give a pale yellow oil which was crude α- [2- (5-bromo-2-methoxy-3-pyridinyl) ethenyl] -3,4-di -klooribentseenimetanolia.

To a stirred mixture of 25.9 g of this crude alcohol in 400 ml of acetic acid under a nitrogen atmosphere was added 25 ml of a 48% aqueous hydrobromic acid solution. The mixture was heated to 85 ° C for about 30 minutes and then rapidly cooled to 23 ° C in an ice bath and partitioned between water and ether. The ether layer was washed several times with water and then with saturated aqueous sodium bicarbonate solution and 83520 sodium chloride solution. It was then dried over sodium sulfate and the solvent was evaporated under reduced pressure to give a pale yellow oil. Filtered through a pad of silica gel 5 using chloroform as eluent to give 6-bromo-2- (3,4-dichlorophenyl) -2H-pyrano [2,3-b] pyridine as a pale yellow solid having the same properties as the material obtained in Example 8.

By repeating the above procedure starting from 10 (E) -3- (5-bromo-2-methoxy-3-pyridinyl) -1- (4-methylphenyl) -2-propen-1-one, the product 6-bromo- 2- (4-methylphenyl) -2H-pyrano [2,3-b] pyridine,

In a similar manner, starting from (E) -3- (5-bromo-2-methoxy-3-pyridinyl) -1- (4-chlorophenyl) -2-15 propen-1-one, 6-bromo-2 - (4-chlorophenyl) -2H-pyrano [2,3-b] pyridine.

Example 11

To a solution of 2.9 g of 6-bromo-2- (3,4-dichlorophenyl) -2H-pyrano [2,3-b] pyridine in 40 ml of tetrahydro-20-furan was added 0.5 ml of 1,8-diazabicyclo [5.4.0] .lundek- 7-enes. After 1 h at 25 ° C, the reaction mixture was partitioned between ethyl acetate and saturated aqueous ammonium chloride solution. The ethyl acetate layer was dried over magnesium sulfate and the solvent was evaporated to leave a solid residue. This was recrystallized from ethanol to give 6-bromo-2- (3,4-dichlorophenyl} -4H-oyrano [2,3-b] pyridine, melting at about 138-139.5 ° C.

Example 12

To a solution of 49.3 g of 6-bromo-2- (3,4-dichloro-30-phenyl) -2H-pyrano [2,3-b] pyridine in 220 ml of anhydrous tetrahydrofuran was added 550 ml of absolute ethanol. The flask containing the solution was rinsed with TV and 60.4 g of an aqueous mixture of W-2 Raney nickel was added. The mixture was then stirred rapidly under a hydrogen atmosphere for a total of 6 hours. The progress of the reaction was monitored by a color spot test. Since the starting material and the product cannot be separated by their own layer a: cg ai; ai J · r: U.:. . tr. c klti r, 2i 83520 doses in a syringe and placed on a TLC plate and developed in 15% ethyl acetate / hexane. The plate was dipped in a 1% solution of p-toluenesulfonic acid in ethanol, wiped dry and heated on a hot le-5 bath for several minutes. The olefinic starting material produces a dark yellow-brown spot and when the color of the spot test was dim yellowish, the reaction was shown to be complete. The hydrogen atmosphere was then replaced with nitrogen and the catalyst was filtered through with methylene chloride throughout, ensuring that the catalyst was covered with the solvent. The filtrate was concentrated under reduced pressure to a small volume, and the formed crystals were separated by filtration. The filtrate was then concentrated and chromatographed to give more solid product. The solid was recrystallized from ethanol to give 6-bromo-2- (3,4-dichlorophenyl) -3,4-dihydro-2H-pyrano [2,3-b] pyridine, melting at about 106-109. ° C. This compound has the following structural formula:

LlKn • N O '

Nci 25 Example 13

By repeating the hydrogenation of Example 12 and using the appropriate starting materials, the following products were obtained: 6-chloro-2- (4-chlorophenyl) -3,4-dihydro-2H-pyrano- [2,3-b] pyridine, m.p. 109-111 ° C; 6-chloro-2- (3,4-dichlorophenyl) -3,4-dihydro-2H-pyrano- [2,3-b] pyridine, m.p. about 106.5 to 107.5 ° C; 6-bromo-3,4-dihydro-2-phenyl-2H-pyrano [2,3-b] pyridine, m.p. about 109-111 ° C; 6-bromo-3,4-dihydro-2- (4-methylphenyl) -2H-pyrano-35 [2,3-b] pyridine, m.p. about 126-127 ° C; and 6-bromo-2- (4-chlorophenyl) -3,4-dihydro-2H-pyrano [2,3-b] pyridine, m.p. about 112.5 to 114 X.

22 83520

Example 14 5-Bromo-2-methoxypyridine-3-carboxaldehyde was reacted with the appropriate acetophenone according to the procedure of Example 7. The resulting ketone was then reduced to the corresponding alcohol and cyclized as described in Example 9. The unsaturated cyclized product was then hydrogenated according to the method of Example 12. In this way, the following products were obtained: 6-bromo-2- (4-bromophenyl) -3,4-dihydro-2H-pvranor-2'-3β-pyridine; 6-bromo-2- (3-chlorophenyl) -3,4-dihydro-2H-pyrano [2,3-b] pyridine; 6-bromo-3,4-dihydro-2- (4-fluorophenyl) -2H-pyrano [2,3-b] pyridine; and 6-bromo-3,4-dihydro-2- (2,4,5-trichlorophenyl) -2H-pyrano-2,3-b] pyridine.

Example 15

A suspension of 23.5 g of 2,5-bis- (methylsulfonyl) pyridine and 200 ml of methanol was prepared, and this mixture was stirred rapidly under a nitrogen atmosphere while 24 ml of 25% sodium methoxide / methanol was added. This mixture was heated to 50 ° C for 20 minutes to give a homogeneous black solution. The solvent was removed by evaporation under reduced pressure, and the resulting product was partitioned between ethyl acetate and water. The ethyl acetate layer was washed with saturated aqueous sodium chloride solution and dried over magnesium sulfate. The mixture was treated with charcoal and filtered through Celite to give a pale yellow filtrate. The filtrate was concentrated under reduced pressure to give a pale yellow oil which solidified on cooling. This was recrystallized from 2-Dropanol to give 2-methoxy-5- (methylsulfonyl) dyridine as colorless crystals; i. about 85-85.5 ° C. This compound was brominated by the method described in Example 2 to give 3-bromo-2-methoxy-5-methylsulfonyl) dyridine; mp.

about 148.5 to 150.5 ° C.

23 8 3 5 2 0

Example 16

A mixture of 2.7 g of 3-bromo-2-methoxy-5- (methylsulfonyl) pyridine, 3.1 g of α-ethenyl-3,4-dichlorobenzenemethanol, 1.3 g of sodium bicarbonate, 10 ml of di -5 methylformamide and 0.11 g of palladium diacetate, stirred under a nitrogen atmosphere and heated to 120 ° C. After 6 hours, thin layer chromatography showed no unreacted bromopyridine starting material. The mixture was then cooled, diluted with ethyl acetate and filtered through Celite. The ethyl acetate solution was washed with water and then twice with saturated aqueous sodium chloride solution and dried over magnesium sulfate. The solution was then filtered and concentrated to a black oil. Excess alcohol was removed by Kugelrohr-dist-15 and the glassy residue was taken up in methylene chloride and chromatographed on silica gel to give a pale yellow solid. This was recrystallized from ethanol / ethyl acetate to give 3- [2-methoxy-5- (methylsulfonyl) -3-pyridyl] -1- (3,4-di-20-chlorophenyl) propan-1-one; mp. about 145-146 ° C.

When 3-bromo-5-chloro-2-methoxypyridine was reacted with α-ethenyl-3,4-dichlorobenzenemethanol according to the above procedure, the product 3- (5-chloro-2-methoxy-3-pyridinyl) -1- (3,4-dichlorophenyl-25-l) propan-1-one, melting at about 81-82.5 ° C.

Example 17

A solution of 0.35 g of 3- (5-chloro-2-methoxy-3-pyridinyl) -1- (3,4-dichlorophenyl) propan-1-one in 4 ml of tetrahydrofuran was added to a rapidly stirred suspension. containing 0.05 g of sodium borohydride in 4 ml of absolute ethanol. After 5 minutes, thin layer chromatography showed complete conversion of the starting material. The reaction mixture was then partitioned between ether and water and the ether layer was washed with saturated aqueous sodium chloride solution, dried over potassium carbonate and concentrated to give a colorless oil which later turned to 24,83520. This product 3- (5-chloro-2-methoxy-3-pyridinyl) -1- (3,4-dichlorophenyl) propan-1-ol (0.32 g) was dissolved in 4 ml of acetic acid and heated to 100 ° To C in a nitrogen atmosphere. 0.5 ml of 48% aqueous hydrobromic acid was then added and heating was continued for 3 hours. The cooled reaction mixture was partitioned between ether and water and the ether layer was extracted twice with saturated aqueous sodium bicarbonate, dried over magnesium sulfate and concentrated to give a colorless oil which later became a solid. The product thus obtained was 6-chloro-2- (3,4-dichlorophenyl) -3,4-dihydro-2H-pyrano [2,3-b] pyridine, which was identical to the substance shown in Example 13.

When the above procedure was repeated using 3- [2-methoxy-5- (methylsulfonyl) -3-pyridinyl] -1- (3,4-dichlorophenyl) propan-1-one, the product 2- (3, 4-dichlorophenyl) -3,4-dihydro-6- (methylsulfonyl) -2H-pyrano [2,3-b] pyridine, melting at about 171.5-173 ° C.

Example 18 3-Bromo-2-methoxy-5- (methylsulfonyl) pyridine is reacted with appropriately substituted α-ethenylbenzenemethanol according to the procedure of Example 16. The resulting ketone was then reduced to the corresponding alcohol with sodium borohydride and the alcohol was treated with hydrobromic acid to effect cyclization, both as described in Example 17. In this way, the following compounds were obtained: 3,4-dihydro-2- (4-methoxyphenyl) -6-methylsulfonyl) -2H-pyrano [2,3-b] pyridine; 3,4-dihydro-2- (3,4-methylenedioxyphenyl) -6- (methylsulfonyl) -2H-pyrano [2,3-b] pyridine, and 3,4-dihydro-6- (methylsulfonyl) -2- (3-phenoxyphenyl) -2H-pyrano [2,3-bipyridine.

25 83520

Example 19

A suspension of 11.75 g of 2,5-bis (methylsulfonyl) pyridine in 100 ml of 20% sulfuric acid was heated under reflux for 2.5 hours. Thin layer 5 chromatography showed complete conversion to the corresponding 2-pyridinone. 14.9 g of potassium iodate was then carefully added to the rapidly stirred reaction mixture while maintaining the temperature at about 90-100 ° C. The exothermic reaction took place releasing iodine. After 30 minutes, 10 g of potassium iodide in 20 ml of water were added dropwise over 1.5 hours. During this addition, a thick precipitate formed. This mixture was allowed to cool to 25 ° C and diluted to 200 mL with water and filtered to collect the precipitate. This precipitate was then washed successively with water, 5% aqueous sodium bisulfate solution, again with water and finally twice with anhydrous ethanol. It was then dried in vacuo to give 3-iodo-5- (methylsulfonyl) -2 (1H) -pyridinone as pale yellow crystals; mp. about 273-276 ° C sa-20 club decomposing.

Example 20

A suspension of 9.0 g of 3-iodo-5- (methylsulfonyl) -2 (1H) -pyridinone in 30 ml of phosphorus oxychloride was heated under reflux under nitrogen for 4 hours to give a homogeneous mixture. This solidified on cooling and the unreacted phosphorus oxychloride was removed under reduced pressure. The resulting white solid residue was dissolved in methylene chloride and extracted first with water and twice with 1N aqueous sodium hydroxide solution.

The mixture was shaken until the aqueous phase remained basic. The methylene chloride solution was then dried over magnesium sulfate and concentrated to leave a white solid residue. This was recrystallized from ethyl acetate / hexane to give 2-chloro-3-iodo-5- (methylsulfon-35-yl) pyridine as colorless needles, melting at about 178.5-180.5 ° C.

26 83520

Example 21

A mixture of 0.85 g of 2-chloro-3-iodo-5- (methylsulfonyl) pyridine, 0.91 g of α-ethenyl-3,4-dichlorobenzenemethanol, 0.77 g of N, N-di -isopropylene ethylamine-5-nia, 0.04 g of tri-o-tolphosphine, 0.02 g of palladium diacetate and 3 ml of dimethylmorphamide were heated to 100 ° C under a nitrogen atmosphere. The mixture was heated at this temperature for 20 minutes and then at 116 ° C for another 20 minutes; at this point, no iodopyridine starting material was detectable by thin layer chromatography.

The mixture was then cooled and partitioned between 1N hydrochloric acid and ethyl acetate. The ethyl acetate layer was washed twice with saturated aqueous sodium chloride solution, imaged with magnesium sulfate and filtered, and the filtrate was concentrated to a dark solid residue. Column chromatography of this residue [silica gel; (1; 1) ethyl acetate / hexane] gave a pale yellow solid. This was recrystallized from ethanol / ethyl acetate to give 3- [2-chloro-5- [methylsulfonyl) -3-pyridinyl] -1- (3,4-dichlorophenyl) propan-1-one, m.p. is about 128.5 to 130.5 ° C.

Example 22

A solution of 0.39 g of 3-L2-chloro-5- (methylsulfonyl) -3-pyridinyl] -1- (3,4-dichlorophenyl) propan-1-one in 15 ml of methylene chloride was cooled. To -70 uC under a nitrogen atmosphere and then a solution of 1.0 ml of 1.5 M diisobutylaluminum hydride / toluene was added dropwise over 3 minutes while maintaining the temperature below -65 ° C. After a further 5 minutes, the mixture was carefully quenched by the addition of 1.5 ml of a mixture of 10% water, 40% acetic acid and 50% ether. The reaction mixture was then allowed to warm to 0 ° C and partitioned between water and methylene chloride. The methylene chloride layer was washed with saturated aqueous sodium bicarbonate solution, dried over magnesium sulfate and filtered, and the filtrate was concentrated to a colorless solid 3- [2-chloro-27,83520 η 5 - (methylsulfonyl) -3-pyridinyl] -1- (3,4-dichlorophenyl) propan-l-ol. This solid was dissolved in 2 mL of anhydrous dimethyl sulfoxide and added to a stirred suspension of 0.07 g of 50% sodium 5 hydride (previously freed from the oil by washing with hexane) in 10 mL of dimethyl sulfoxide under a nitrogen atmosphere. Gas release occurred and the mixture became first lavender and then cherry red. After 15 minutes, it was partitioned between ethyl acetate and 1 N hydrochloric acid. The yellow ethyl acetate layer was washed with water and then twice with saturated aqueous sodium chloride solution, dried over magnesium sulfate and filtered, and the filtrate was concentrated to leave a pale yellow solid. This solid was recrystallized from a mixture of 2-propanol and ethyl acetate to give 2- (3,4-dichlorophenyl) -3,4-dihydro-6- (methylsulfonyl) -2H-pyrano [2,3-b] pyridine, m.p. . is about 171.5 to 172.5 ° C. This material had the same spectral properties as the material prepared by the method described in Example 17 Brochure-20. This compound has the structure of the following formula: CH, SO 2? 'tXXQ ~ ^ Cl

Example 23

A solution of 3.6 g of 6-bromo-2- (3,4-dichlorophenyl) -3,4-dihydro-2H-pyrano [2,3-b] pyridine in 50 ml of toluene and 25 ml of anhydrous ether, cooled to 190 ° C under a nitrogen atmosphere, and 3.8 ml of 2.9 M tert-butyllithium / pentane was added dropwise over about 5 minutes while maintaining the temperature below -100 ° C.

35 This gave a blue-green mixture with a lithium intermediate (i.e. lithium replaces bromine in the starting material). After 20 minutes, 1.8 ml of dimethyl sulfide was added. The mixture was then allowed to warm to 0 ° C and partitioned between ether and water. The ether layer was washed with saturated aqueous sodium chloride solution, dried over potassium carbonate and concentrated to a yellow oil which solidified on cooling. Column chromatography on silica gel (20% ethyl acetate / hexane) gave the pure product, which was further recrystallized from hexane / ethyl acetate to give 2-3,4-dichlorophenyl) -3,4-dihydro-6- (methylthio) -2H-pyranoL2. , 3-bJ pyridine as colorless crystals of m.p. is about 103-111 ° C.

Repeating the above procedure using the appropriate starting bromine compounds gave the following compounds: 2- (4-chlorophenyl) -3,4-dihydro-6- (methylthio) -2H-pyrano-15 [2,3-b] pyridine, m.p. about 103-105 ° C, and 3,4-dihydro-6- (methylthio) -2-phenyl-2H-pyrano [2,3-b] pyridine, m.p. about 105-107 ° C.

Example 24 6-Bromo-2- (3,4-dichlorophenyl) -3,4-dihydro-2H-pyrrano [2,3-b] pyridine (1.5 g) was converted to the lithium intermediate by the method of Example 23. and then quenched at -85 ° C with excess methanol. Chromatographic purification of the crude product gave 2- (3,4-dichlorophenyl) -3,4-dihydro-2H-pyrano [2,3-b] pyridine as a cream solid which melted at about 99-100 ° C. Example 25 6-Bromo-2- (3,4-dichlorothienyl) -3,4-dihydro-2H-pyrano [2,3-b] pyridine (0.85 a) was converted to as a lithium intermediate by the method described in Example 23 and then quenched at -95 ° C with excess n-butyl disulfide.

Chromatographic purification of the crude product gave a powdery white solid which was further recrystallized from ethyl acetate / hexane to give 6- (n-butylthio) -2- (3,4-dichlorophenyl) -3,4-di-35 hydro-2H-pyrano [2 , 3-blDridine, melting at about 59.5-61 uC.

29 8 3 5 2 0

Example 26 6-Bromo-2- (3,4-dichlorophenyl) -3,4-dihydro-2H-pyrano [2,3-b] pyridine (1.3 g) was converted to the corresponding lithium intermediate by the method described in Example 23. and then quenched at -100 ° C with a solution of 0.8 g of benzonitrile in 4 ml of toluene. The crude product was isolated as in Example 23 and purified by chromatography [silica gel; (2: 1) hexane / ethyl acetate] to give 6-benzoyl-2- (3,4-10 dichlorophenyl) -3,4-dihydro-2H-pyrano [2,3-b] pyridine, m.p. - 158 ° C.

Example 27 6-Bromo-2- (3,4-dichlorophenyl) -3,4-dihydro-2H-pyrano [2,3-b] pyridine (1.5 g) was converted to the corresponding lithium intermediate by the method described in Example 23. and then quenched at -90 ° C with 1.3 mL of tri-n-butyl borate. The resulting dark solution was stirred at -75 ° C for 2 hours and then allowed to warm to 0 ° C. The mixture was then acidified with 3N hydrochloric acid, the organic phase was separated and the aqueous layer was extracted with ether. The combined organic layers were concentrated to give a light brown, sticky solid. To this was added 25 ml of 30% hydrogen peroxide, and the resulting mixture was heated at 60 ° C for 30 minutes. The mixture was then cooled and diluted with 75 ml of water, and the resulting mixture was extracted twice with 50 ml of methylene chloride. The methylene chloride extracts were combined, washed with saturated aqueous sodium chloride, dried over sodium sulfate and concentrated to give a yellow solid. Thin layer chromatography [silica gel; 3% ethyl acetate / hexane] gave 2- (3,4-dichlorophenyl) -3,4-dihydro-6-hydroxy-2H-pyrano [2,3-b] pyridine, m.p. is about 218-219 ° C.

Example 28 35 6-Bromo-2- (3,4-dichlorophenyl) -3,4-dihydro-2H-pyrano [2,3-b] pyridine (14.4 g) in a mixture with 400 ml 30,83520 toluene and 200 ml of ether were converted to the corresponding lithium intermediate as described in Example 23. The lithium intermediate was quenched at -100 ° C by the addition of 10.8 mL of methyl disulfide. The mixture was then allowed to warm to -50 ° C and partitioned between water and ether. The aqueous layer was extracted with ether and the combined organic layers were washed with saturated aqueous sodium chloride, dried over potassium carbonate and filtered, and the filtrate was concentrated in vacuo to give a dark yellow oil which later became a solid. The crude thioether thus obtained was dissolved in 80 ml of tetrahydrofuran, diluted with 160 ml of methanol and cooled in an ice-water bath while adding a solution of 49.2 g of potassium peroxymonosulfuric acid in 150 ml of water at such a rate that the temperature remained below 30 ° C. A thick white precipitate formed and effective mechanical stirring was necessary. After 3 hours, the mixture was poured into 1 liter of water and extracted with ethyl acetate. The aqueous layer was further extracted with ethyl acetate, and the combined organic layers were washed with saturated aqueous sodium chloride solution, dried over magnesium sulfate and filtered, and the filtrate was concentrated to give a yellow solid. This solid was recrystallized from a mixture of 2-propanol and ethyl acetate to give 2- (3,4-dichlorophenyl) -3,4-dihydro-6-methylsulfonyl) -2H-pyrano [2,3-b] pyridine, m.p. At 173.5 ° C. The product was identical in all respects to the substance prepared according to the methods described in the previous examples.

By repeating the above procedure using the appropriate starting materials, the following compounds were obtained: 2- (4-chlorophenyl) -3,4-dihydro-b-methylsulfonyl) -2H-ovranof 2,3-b] pyridine, m.p. about 187-189 ° C, and 3,4-dihydro-6- (methylsulfonyl) -2-phenyl-2H-pyrano-35β-pyridine. mp. about 188-189 ° C.

31 83520

Example 29

To a stirred solution of 1.0 g of 2- (3,4-dichlorophenyl) -3,4-dihydro-6- (methylthio) -2H-pyrano- [2,3-b] pyridine in 25 ml of methylene chloride -25 At 0.5 ° C, a solution of 0.55 g of 80-89% m-chloroperoxybenzoic acid in 20 ml of methylene chloride was added dropwise over 5-10 minutes while maintaining the temperature at -20 to -30 ° C. A precipitate formed. The mixture was then allowed to warm to -5 ° C over 2 hours and then extracted with saturated aqueous sodium bicarbonate solution and saturated aqueous sodium chloride solution, dried over sodium sulfate and concentrated in vacuo to leave a pale yellow solid. This was repeated from a mixture of ethyl acetate and hexane to give 2- (3,4-dichlorophenyl) -3,4-dihydro-6- (methylsulfinyl) -2H-pyrano [2,3-b] pyridine as a cream as a solid melting at about 159-162 ° C.

Example 30

To a stirred solution of 1.9 g of 3- (5-20 chloro-2-methoxy-3-pyridinyl) -1- (3,4-dichlorophenyl) propan-1-one in 55 ml of anhydrous tetrahydrofuran at 5 ° C in a nitrogen atmosphere, 2.6 ml of 2.9 M methylmagnesium chloride / tetrahydrofuran was added via syringe over a period of about 10 minutes. The resulting yellow mixture was allowed to warm to 23 ° C and after 2 hours was quenched by the careful addition of 20 mL of 0.05 N hydrochloric acid. The mixture was then poured into 50% water and extracted twice with ether. The combined extracts were washed with water and saturated aqueous sodium chloride solution, and then dried over sodium sulfate. The solvent was removed under reduced pressure to leave a yellow oil with the expected spectrum for alcohol.

To a solution of 1.15 g of this alcohol in 25 ml of acetic acid under a nitrogen atmosphere was added 1.2 ml of 48% hydrobromic acid. The solution was then stirred and heated to 100 ° C. After 10 minutes, the 32,83520 solution was cooled to 25 ° C and partitioned between ether and water. The ether layer was washed with saturated aqueous sodium bicarbonate solution (twice) and then with saturated aqueous sodium chloride solution, dried over magnesium sulfate and concentrated to a viscous orange oil. This was subjected to column chromatography [silica gel; initially 5% ethyl acetate / hexane, then 7% ethyl acetate / hexane and finally (1: 1) ethyl acetate / hexane j. The lower Rf fraction was then subjected to preparative thin layer chromatography (15% ethyl acetate / hexane) to give a colorless oil. This was further triturated with hexane to give, after removal of the supernatant, a white granular solid melting at about 83-84 ° C which was 6-chloro-2- (3,4-dichlorophenyl) -3,4- dihydro-2-methyl-2H-pyrano [2,3-b] pyridine.

Claims (13)

33 8 3 520 A process for the preparation of a therapeutically useful compound of formula I wherein R, R 'and R "are each hydrogen or lower alkyl of 1 to 4 carbon atoms; 15. is hydrogen, chlorine, bromine, alkylthio, alkylsulfinyl, alkylsulfonyl, hydroxy or benzoyl; and Y is hydrogen, halo, di- or trichloro, alkyl, alkoxy, methylenedioxy or phenoxy; characterized in that a suitable alcohol having the following structural formulas R "OH R (II) R 'and OH 30 L 11 (where N, N, R, R' and R "are the same as defined above and Q is methoxy or chlorine are cyclized using hydrobromic acid and acetic acid to 2-methoxypyridines 34 83520 or a strong base when Q is chlorine, followed optionally, if the product obtained is a compound having a double bond at the 3,4-position, is catalytically reduced with hydrogen and Raney nickel to give the corresponding saturated compounds. A process for preparing a compound of formula 10 according to claim 1, wherein X is hydrogen, chlorine, bromine, alkylthio, alkylsulfinyl, alkylsulfonyl, hydroxy or benzoyl, Y is hydrogen, halo, di- or trichloro, alkyl, alkoxy, methylenedioxy or phenoxy; characterized in that a suitable alcohol of the following structural formulas 20 OH ΤΓ I (VII) '25 OH t ΊΤ 30 ^ nAoch3 ^ (III) in which X and Y are as defined above and Q is 35 methoxy or chlorine is cyclized using hydrobromic acid -po and acetic acid to 2-methoxypyridines or a strong base when Q is chlorine, followed by catalytic reduction with hydrogen and Raney-Nikke if the product obtained is a compound with a double bond at the 3,4-position. -lillä. A process for the preparation of a compound of the formula <XXn> 10 -> \ * according to claim 1, wherein X "is chlorine, bromine or methylsulphonyl and Y" is chlorine or dichloro, characterized in that a suitable alcohol having have the following structural formulas OH (VIII) 20 'S Ij II -J-Y "^ n ^ och3 and OH 25 X * l> V ^ || '\ Ly * (IX> ^ n ^ θ (: ο3 30 wherein X "and Y" are as defined above, cyclized using hydrobromic acid and acetic acid, followed, if the product obtained is a compound having a double bond 3, In the 4-position, catalytically reduced with 35 hydrogen and Raney nickel 36 83520 Process for the preparation of a compound of formula C1C (IC) Nc10 according to claim 1, wherein X "is chlorine, bromine or methylsulphonyl, characterized in that a suitable alcohol of the following structural formulas OH 15 I II I (x) iL - ci ^ OCH3 Cl and 20 OH x 'Λ 1 _ ^ "Y Tf jj Ί <XI> v N ^ OCH3 n 25 where X" is the same as defined above, is cyclized using hydrobromic acid and acetic acid, followed, if the product obtained is a compound having a double bond 3 , In the 4-position, is catalytically reduced with hydrogen and Ra-30 ney-nickel. Process for the preparation of 6-bromo-2- (3,4-dichlorophenyl) -3,4-dihydro-2H-pyrano [2,3-b] pyridine according to Claim 1, characterized in that (E) - 5-Bromo-α- [2- (3,4-dichlorophenyl) ethenyl] -2-methoxy-3-pyridinemethanol is reacted with hydrobromic acid and acetic acid, after which the product obtained is catalytically reduced with hydrogen and Raney nickel S. 37 83520 Process for the preparation of 6-bromo-2- (3,4-dichlorophenyl) -3,4-dihydro-2H-pyrano [2,3-b] pyridine according to Claim 1, characterized in that α- [2 - (5-bromo-2-methoxy-3-pyridinyl) ethenyl] -3,4-dichlorobenzenemethanol is reacted with hydrobromic acid and acetic acid, after which the product obtained is catalytically reduced with hydrogen and Raney nickel. Process for the preparation of 6-chloro-2- (3,4-dichlorophenyl) -3,4-dihydro-2H-pyrano-10,3,3-b-pyridine according to Claim 1, characterized in that (E) -5-chloro-α- [2- (3,4-dichlorophenyl) ethenyl] -2-methoxy-3-pyridinemethanol is reacted with hydrobromic acid and acetic acid, after which the product obtained is catalytically reduced with hydrogen and Raney-Nikke-15. . Process for the preparation of 6-chloro-2- (3,4-dichlorophenyl) -3,4-dihydro-2H-pyrano [2,3-b] pyridine according to Claim 1, characterized in that 3- (5 -Chloro-2-methoxy-3-pyridinyl) -1- (3,4-di-20-chlorophenyl) propan-1-ol is reacted with hydrobromic acid and acetic acid. Process for the preparation of 2- (3,4-dichlorophenyl) -3,4-dihydro-6- (methylsulfonyl) -2H-pyrano [2,3-b] pyridine according to Claim 1, characterized in that 3- (5-Methylsulfonyl-2-methoxy-3-pyridinyl) -1- (3,4-dichlorophenyl) propan-1-ol is reacted with hydrobromic acid and acetic acid. Process for the preparation of 2- (3,4-dichlorophenyl) -3,4-dihydro-6- (methylsulfonyl) -30 2H-pyrano [2,3-b] pyridine according to Claim 1, characterized in that 3- [2-Chloro-5- (methylsulfonyl) -3-pyridinyl] -1- (3,4-dichlorophenyl) propan-1-ol is reacted with a strong base. Process for the preparation of 6-35 bromo-2- (4-chlorophenyl) -3,4-dihydro-2H-pyrano [2,3-b] pyridine according to Claim 1, characterized in that α- [2- ( 5-Bromo-2-methoxy-3-pyridinyl Jetenyl] -4-chlorobenzenemethanol is reacted with hydrobromic acid and 38 8 3 5 2 0 acetic acid, after which the product obtained is catalytically reduced with hydrogen and Raney nickel. Process for the preparation of 6-chloro-2- (4-chlorophenyl) -3,4-dihydro-2H-pyrano [2,3-b] pyridine according to Claim 1, characterized in that (E) -5- chloro-α- [2- (4-chlorophenyl) ethenyl] -2-methoxy-3-pyridinemethanol is reacted with hydrobromic acid and acetic acid, after which the product obtained is catalytically reduced with hydrogen and Raney nickel. Process according to Claim 1, characterized in that 2- (4-chlorophenyl) -3,4-dihydro-6- (methylsulfonyl) -2H-pyrano [2,3-b] pyridine is prepared; 2- (3,4-dichlorophenyl) -3,4-dihydro-6- (methylthio) -2H-pyrano [2,3-b] pyridine; 2- (3,4-dichlorophenyl) -3,4-dihydro-6-methylsulfinyl) -2H-pyrano [2,3-b] pyridine, or 2- (4-chlorophenyl) -3,4-dihydro-6- (methylthio) -2H-pyrano [2,3-b] pyridine. 39 83520